磷酸化改变 Bim 介导的 Mcl-1 稳定和引发。
Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming.
机构信息
Cancer Biology Graduate Program, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
出版信息
FEBS J. 2018 Jul;285(14):2626-2640. doi: 10.1111/febs.14505. Epub 2018 May 29.
Mcl-1 is a highly labile protein, subject to extensive post-translational regulation. This distinguishes Mcl-1 from other antiapoptotic proteins and necessitates further study to better understand how interactions with proapoptotic Bcl-2 proteins affect its regulation. One such protein, Bim, is known to stabilize Mcl-1, and Bim phosphorylation has been associated with increased Mcl-1 binding. Consequently, we investigated the potential impact of Bim phosphorylation on Mcl-1 stability. We found that Bim stabilizes and primes Mcl-1 in RPCI-WM1 cells and is constitutively phosphorylated. Additionally, introduction of several phospho-mimetic and unphosphosphorylateable Bim mutations resulted in altered Mcl-1 stability and distinct Bim binding to antiapoptotic proteins. These findings suggest Bim phosphorylation not only regulates Mcl-1 stability but also is a potential mechanism for enforcing Mcl-1 dependence.
Mcl-1 是一种高度不稳定的蛋白质，受到广泛的翻译后调节。这使其有别于其他抗凋亡蛋白，并需要进一步研究以更好地了解与促凋亡 Bcl-2 蛋白的相互作用如何影响其调节。一种这样的蛋白，Bim，已知可以稳定 Mcl-1，并且 Bim 的磷酸化已与增加的 Mcl-1 结合相关。因此，我们研究了 Bim 磷酸化对 Mcl-1 稳定性的潜在影响。我们发现 Bim 在 RPCI-WM1 细胞中稳定和激活 Mcl-1，并且是组成性磷酸化的。此外，引入几种磷酸模拟和非磷酸化 Bim 突变导致 Mcl-1 稳定性的改变以及抗凋亡蛋白与 Bim 的不同结合。这些发现表明 Bim 磷酸化不仅调节 Mcl-1 的稳定性，而且是强制依赖 Mcl-1 的潜在机制。
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